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The mission of the Clinical Trials Transformation Initiative (CTTI) is To develop and drive adoption of practices that will increase the quality and efficiency of clinical trials. CTTI’s 10th Year Anniversary will be celebrated in Washington on February 5-6, 2018.

Target Health Inc. has supported the CTTI Mission since joining CTTI on 8 August 2008, and we congratulate CTTI for its major contribution to the clinical trials enterprise over the past 10 years. When we joined in 2008, our friend and colleague Dr. Judith Kramer wrote this in response to our commitment to join: Likewise; I really enjoyed our conversation. I am very pleased that you decided to join CTTI as I think you will be an extremely valuable participant at the “table”.

As part of Target Health commitment to the CTTI Mission, Jules Mitchel, President of Target Health was honored to serve on the Executive Committee of CTTI representing the Steering Committee, and was one of the authors of the 2011 publication on “Monitoring the quality of conduct of clinical trials: a survey of current practices.” This seminal CTTI publication was coauthored by: Briggs W Morrison, Chrissy J Cochran, Jennifer Giangrande White, Joan Harley, Cynthia F Kleppinger, An Liu, Jules T Mitchel, David F Nickerson, Cynthia R Zacharias, Judith M Kramer, James D Neaton. The esteemed Target Health software development team also created the database used to collect the survey information.

A major highlight last year was a joint NIH Collaboratory Grand Rounds Webinar presented with John Laschinger, CDRH/FDA and Jules Mitchel: entitled CTTI Registry Trials Project: Evaluation and Design of Registries for Conducting Clinical Trials.

Current projects that Target Health is actively involved with include Mobile Devices and Registries. There is an interview of Dr. Mitchel on the CTTI website.

CTTI, a public-private partnership with FDA’s Office of Critical Path Programs and Duke University, is mandated to bring together all interested stakeholders in order to identify practices that, through broad adoption, will increase the quality and efficiency of clinical trials. It is envisioned that this group will seek out new methods and technologies that improve safety, enhance the quality of information from trials, and make the research process more efficient. CTTI will identify best practices, conduct empirical research, and develop new standards for future research efforts. .

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

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Listening to music first involves subcortical structures like cochlear nuclei, the brain stem, and the cerebellum. It then moves up to auditory cortices on both sides of the brain. And when you hear music, listening also involves the memory centers in the brain, such as the hippocampus and lowest parts of the 1) ___ ____. Tapping along with the music gets your cerebellum involved. Reading music involves the visual cortex and listening to or recalling lyrics will involve language centers in the temporal and frontal lobes. If you actually perform music, your frontal lobe for planning, and your motor and sensory cortex will activate as well. Because playing music requires co-ordination of motor control, somatosensory touch and auditory information, most musicians are known to have developed a greater ability than the average person to use both hands. Increased networks between the left and right brain form thick fibers that interconnect the two motor areas, an area that is larger in musicians than in non-2) ___. Because the brain has the capacity to change (called neuroplasticity), music also affects some of the brain’s learning capacities, increasing the size of the auditory and motor 3) ___. A research team from Utrecht University in the Netherlands also found music is associated with an improved ability for auditory imagery. Musically trained groups performed better on both a musical imagery task and a non-musical auditory-imagery task than naive groups.

An earworm, sometimes known as a brainworm, sticky music, stuck song syndrome, or Involuntary Musical Imagery (INMI) is a catchy piece of music that continually repeats through a person’s mind after it is no longer 4) ___. Phrases used to describe an earworm include “musical imagery repetition”, “involuntary musical imagery”, and “stuck song syndrome”. The word earworm is possibly a calque from the German Ohrwurm. Mark Twain chronicled the experience of earworms in his short story “A Literary Nightmare,” published in an 1876 edition of The Atlantic Monthly. This story describes the gradual 5) ___ possession of an entire community by a catchy jingle that gets stuck in a mental groove, over and over again, in all of their imaginations.

Researchers who have studied and written about the phenomenon include Theodor Reik, Sean Bennett, Oliver Sacks, Daniel Levitin, James Kellaris, Philip Beaman, Vicky Williamson, and, in a more theoretical perspective, Peter Szendy. The phenomenon is common and should not be confused with palinacousis, a rare medical condition caused by damage to the temporal 6) ___ of the brain that results in auditory hallucinations. Vicky Williamson at Goldsmiths, University of London, found in an uncontrolled study that earworms correlated with music exposure (having heard the song recently or frequently), but could also be triggered by experiences that trigger the memory of a song (involuntary memory) such as seeing a word that reminds one of the song, hearing a few notes from the song, or feeling an emotion one associates with the 7) ___. The list of songs collected in the study showed no particular pattern, other than popularity. According to James Kellaris, 98% of individuals experience earworms. Women and men experience the phenomenon equally often, but earworms tend to last longer for women and irritate them more. Kellaris produced statistics suggesting that songs with lyrics may account for 73.7% of earworms, whereas instrumental music may cause only 7.7%. In 2010, published data in the British Journal of Psychology directly addressed the subject, and its results support earlier claims that earworms are usually 15 to 30 seconds in length and are more common in those with an interest in music.

Scientists at Western Washington University found that engaging working memory in moderately difficult tasks (such as anagrams, Sudoku puzzles, or reading a novel) was an effective way of stopping earworms and of reducing their recurrence. Another publication points out that melodic music has a tendency to demonstrate repeating rhythm which may lead to endless repetition, unless a climax can be achieved to break the cycle. Research reported in 2015 by the School of Psychology and Clinical Language Sciences at the University of Reading demonstrated that, over the short-term, chewing gum could help by similarly blocking the sub-vocal rehearsal component of auditory short-term or “working” memory associated with generating and manipulating auditory and musical images.

Involuntary semantic memories are a new topic in psychology. Initial research has suggested that musical memories are a dominant type of involuntary 8) ___. Interestingly, no comprehensive information exists on the commonality of earworms, or repeated involuntary imagery of music (INMI), and its relationship to the engagement with musical activities. A recent study investigated these, using cross-sectional, retrospective reports from a questionnaire study that was conducted among Finnish internet users (N = 12,519). The analyses of the Finnish data revealed that 89.2% of participants reported experiencing this phenomenon at least once a week. The amount of music practice and listening was positively related to the frequency of involuntary music. Women reported elevated levels of involuntary imagery episodes in contrast to men, who reacted differently. In older age-groups the frequency of the incidents decreased among both sexes. People with extensive, musical practice history, seemed to experience longer musical segments and more often instrumental ones. They were less agitated by involuntary music and reported it less often. The results are discussed in relation to a memory-based hypothesis of involuntary musical imagery. In conclusion, INMI is viewed as an integral part of our musical mind. INMI appears to be a part of disparate cultures around the world. In episode 20 of season 7 of SpongeBob SquarePants, entitled “Ear Worm” (2010), SpongeBob gets a song stuck in his head called “Musical Doodle”. The episode refers to the 9) ___ as a physical creature that enters one’s head upon one’s listening to a catchy song.

In 1943 Henry Kuttner published the short story “Nothing but Gingerbread Left” about a song engineered to damage the Nazi war effort, culminating in Adolf Hitler being unable to continue a speech. In Alfred Bester’s 1953 novel The Demolished Man, the protagonist uses a jingle specifically crafted to be a catchy, irritating nuisance as a tool to block mind readers from reading his mind. In Arthur C. Clarke’s 1957 science fiction short story “The Ultimate Melody”, a scientist, Gilbert Lister, develops the ultimate melody – one that so compels the brain that its listener becomes completely and forever enraptured by it. Lister theorized that a great melody “made its impression on the mind because it fit in with the fundamental electrical rhythms going on in the 10) ___.” Lister attempts to abstract from the hit tunes of the day to a melody that fits in so well with the electrical rhythms that it dominates them completely. He succeeds and is found in a catatonic state from which he never awakens.

Santiago Ramon y Cajal was a Spanish neuroscientist and pathologist, specializing in neuroanatomy, particularly the histology of the central nervous system. He won the Nobel prize in 1906, becoming the first person of Spanish origin who won a scientific Nobel prize. His original investigations of the microscopic structure of the brain made him a pioneer of modern neuroscience. Hundreds of his drawings illustrating the delicate arborizations of brain cells are still in use for educational and training purposes.

Santiago Ramon y Cajal was born 1 May 1852 in the town of Petilla de Aragon, Navarre, Spain. His father was an anatomy teacher. As a child, he was transferred many times from one school to another because of behavior that was declared poor, rebellious, and showing an anti-authoritarian attitude. An extreme example of his precociousness and rebelliousness at the age of eleven is his 1863 imprisonment for destroying his neighbor’s yard gate with a homemade cannon. He was an avid painter, artist, and gymnast, but his father neither appreciated nor encouraged these abilities, even though these artistic talents would contribute to his success later in life. In order to tame the unruly character of his son, his father apprenticed him to a shoemaker and barber.

Over the summer of 1868, his father hoped to interest his son in a medical career, and took him to graveyards to find human remains for anatomical study. Sketching bones was a turning point for him and subsequently, he did pursue studies in medicine. Ramon y Cajal attended the medical school of the University of Zaragoza, where his father was an anatomy teacher. He graduated in 1873, aged 21. After a competitive examination, he served as a medical officer in the Spanish Army. He took part in an expedition to Cuba in 1874-75, where he contracted malaria and tuberculosis. In order to heal, he visited the Panticosa spa-town in the Pyrenees. After returning to Spain, he received his doctorate in medicine in Madrid in 1877. In 1879, he became the director of the Zaragoza Museum, and he married Silveria Fananas Garc?a, with whom he had four daughters and three sons. Cajal worked at the University of Zaragoza until 1883, when he was awarded the position of anatomy professor of the University of Valencia. His early work at these two universities focused on the pathology of inflammation, the microbiology of cholera, and the structure of epithelial cells and tissues.

In 1887 Cajal moved to Barcelona for a professorship. There he first learned about Golgi’s method, a cell staining method which uses potassium dichromate and silver nitrate to (randomly) stain a few neurons a dark black color, while leaving the surrounding cells transparent. This method, which he improved, was central to his work, allowing him to turn his attention to the central nervous system (brain and spinal cord), in which neurons are so densely intertwined that standard microscopic inspection would be nearly impossible. During this period he made extensive detailed drawings of neural material, covering many species and most major regions of the brain. In 1892, he became a professor in Madrid. In 1899 he became director of the National Institute of Hygiene , and in 1922 founder of the Laboratory of Biological Investigations , later renamed to the Cajal Institute. He died in Madrid on October 17, 1934, at the age of 82, continuing to work even on his deathbed.

Ramon y Cajal made several major contributions to neuroanatomy. He discovered the axonal growth cone, and demonstrated experimentally that the relationship between nerve cells was not continuous, but contiguous. This provided definitive evidence for what Heinrich Waldeyer coined the term neuron theory as opposed to the reticular theory This is now widely considered the foundation of modern neuroscience. Cajal was an advocate of the existence of dendritic spines, although he did not recognize them as the site of contact from presynaptic cells. He was a proponent of polarization of nerve cell function and his student, Rafael Lorente de N?, would continue this study of input-output systems into cable theory and some of the earliest circuit analysis of neural structures. By producing excellent depictions of neural structures and their connectivity and providing detailed descriptions of cell types he discovered a new type of cell, which was subsequently named after him, the interstitial cell of Cajal (ICC). This cell is found interleaved among neurons embedded within the smooth muscles lining the gut, serving as the generator and pacemaker of the slow waves of contraction which move material along the gastrointestinal tract, mediating neurotransmission from motor neurons to smooth muscle cells. In his 1894 Croonian Lecture, Ramon y Cajal suggested (in an extended metaphor) that cortical pyramidal cells may become more elaborate with time, as a tree grows and extends its branches.

Cajal devoted a considerable amount of time studying hypnosis which he used to help his wife during labor and parapsychological phenomena. A book he had written on these topics was lost during the Spanish Civil War. Cajal received many prizes, distinctions, and societal memberships during his scientific career, including honorary doctorates in medicine from Cambridge University and Wurzburg University and an honorary doctorate in philosophy from Clark University in the United States. The most famous distinction he was awarded was the Nobel Prize in Physiology or Medicine in 1906, together with the Italian scientist Camillo Golgi in recognition of their work on the structure of the nervous system. This caused some controversy because Golgi, a staunch supporter of reticular theory, disagreed with Ramon y Cajal in his view of the neuron doctrine. He published more than 100 scientific works and articles in Spanish, French and German. Among his most notable works were:

In 1905, he published five science-fiction stories called Vacation Stories under the pen name Dr. Bacteria.

The asteroid 117413 Ramonycajal has been named in his honor.

In the 21st Century:

In 2014, the National Institutes of Health exhibited original Ramon y Cajal drawings in its Neuroscience Research Center.

This year 2018:

An exhibition called The Beautiful Brain: The Drawings of Santiago Ramon y Cajal travelled through the US beginning 2017 at the Weisman Art Museum in Minneapolis ending April 2019 at the Ackland Art Museum in Chapel Hill, North Carolina.

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According to a study published online in Science Translational Medicine (24 January 2018), for the first time, a relationship has been shown between health outcomes and the proportion of key immune cells, at the time of HIV infection, that display high levels of a gut-homing protein called alpha-4 beta-7. Previous research illustrated this relationship in monkeys infected with a simian form of HIV. The new study found that women who had more CD4+ T cells displaying high levels of alpha-4 beta-7 on their surface were more likely to become infected with HIV, and the virus damaged their immune systems more rapidly, than women with fewer such cells. The National Institutes of Health co-funded the study with the South African Medical Research Council as part of the U.S.-South Africa Program for Collaborative Biomedical Research.

For the study, the authors compared the percentage of CD4+ T cells displaying high levels of alpha-4 beta-7 in blood samples drawn from 59 women shortly before they acquired HIV to the percentage of such cells in 106 women who remained HIV negative. The women, 18 to 40 years of age, were selected from participants in the CAPRISA 004 study, which evaluated the safety and efficacy of tenofovir gel for HIV prevention in KwaZulu-Natal, South Africa, from 2007 to 2010. Understanding HIV acquisition and disease progression among African women is especially important because women accounted for nearly 60% of new HIV infections among adults in sub-Saharan Africa in 2016.

Results showed that the proportion of CD4+ T cells with high levels of alpha-4 beta-7 had an effect, albeit modest, on the risk of acquiring HIV among both the women in the CAPRISA 004 study and a separate cohort of 41 high-risk females in Kenya. The risk of HIV acquisition rose by 18% for each 1% increase in alpha-4 beta-7 protein. The authors showed a similar association in monkeys that were exposed to a simian form of HIV. The proportion of CD4+ T cells with high levels of alpha-4 beta-7 strongly affected how quickly HIV damaged the immune system. CD4+ T cell levels declined twice as fast among women with higher pre-infection levels of alpha-4 beta-7 as among women with lower pre-infection levels. In addition, the amount of HIV in the blood within a few months of infection was greater in women with higher pre-infection levels of alpha-4 beta-7 than in women with lower pre-infection levels. According to the authors, the mechanism for the immune system damage likely was HIV-related damage to the gut, as higher pre-infection levels of alpha-4 beta-7 were associated with higher levels of a biological marker of gut damage. The authors also found that HIV targets CD4+ T cells displaying alpha-4 beta-7 very early in infection, particularly in the gut. In this regard, the authors looked at data from the U.S. Military HIV Research Program-led RV254 clinical trial at the Thai Red Cross in Bangkok, Thailand, and found that starting antiretroviral therapy (ART) right after HIV diagnosis did not prevent the depletion of CD4+ T cells from the gut or facilitate reconstitution of the depleted cells. According to the authors, these findings suggest that interventions in addition to ART may be needed to restore CD4+ T cells in the GI tracts of people living with HIV, and that one such intervention could be an anti-alpha-4 beta-7 antibody called vedolizumab, which is FDA-approved for the treatment of ulcerative colitis and Crohn’s disease.

In previous studies, a monkey-adapted form of vedolizumab contributed to the near-replenishment in monkeys of CD4+ T cells that had been destroyed by a simian form of HIV. Based on this and related findings, NIAID initiated an early-phase clinical trial in 2017 to determine whether short-term treatment with vedolizumab in combination with ART could generate sustained HIV remission in people living with HIV. The study is taking place at the NIH Clinical Research Center in Bethesda, Maryland. Preliminary results are expected later this year. More information about the study is available at ClinicalTrials.gov under study identifier NCT02788175.

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According to a study published in mBio (23 January 2018), people with higher levels of antibodies against the stem portion of the influenza virus hemagglutinin (HA) protein have less viral shedding when they get the flu, but do not have fewer or less severe signs of illness. HA sits on the surface of the influenza virus to help bind it to cells and features a head and stem region. It has only recently been discovered that humans naturally generate anti-HA stem antibodies in response to flu infection, and this is the first study of its kind to evaluate pre-existing levels of these specific antibodies as a predictor of protection against influenza. The findings could have implications for flu vaccine development, according to the authors.

Because the head region of HA is constantly changing, influenza vaccine strains must be updated each year. The HA stem region, however, is less susceptible to change, making it a potential target for novel vaccines aimed at broader, more durable protection. Therefore, the authors explored immune responses to two influenza surface proteins: HA — the main target of traditional seasonal flu vaccines — and neuraminidase (NA).

For the study, the authors sought to understand the role of pre-existing anti-HA stem antibodies in protection against influenza using data from a healthy volunteer influenza challenge trial that took place in 2013 at the NIH Clinical Center in Bethesda, Maryland. The clinical trial enrolled 65 healthy volunteers aged 18 to 50 years and study participants stayed in a specially designed isolation and infection control unit throughout the study. The authors measured participants’ baseline levels of anti-HA stem antibodies, infected them with a 2009 H1N1 influenza virus, and then measured levels of anti-HA stem antibodies again. Results showed that all volunteers had anti-HA stem antibodies at baseline, although levels varied, and 64% of participants had increased levels after infection. However, people with higher levels before exposure had smaller increases, suggesting there could be a limit that humans can achieve naturally. Trial investigators also closely monitored participants’ symptoms and the amount of influenza virus they shed from the nose, which may indicate how contagious someone is. Similar to findings regarding anti-HA head antibodies, it was found that participants with higher baseline levels of anti-HA stem antibodies had reduced viral shedding, but no significant reduction in the duration or severity of illness.

The results show that people naturally make anti-HA stem antibodies, but that responses vary significantly, and also these antibody levels are not independent predictors of whether someone becomes sick or if so, how severely. The authors note that antibodies against NA remain the only identified predictor of disease severity, according to previously reported trial data. Although the data are limited, the results have implications for novel influenza vaccine design, according to the authors. They note future strategies ideally should focus on more than one aspect of immunity and that careful consideration of the complexity of influenza immune protection and evaluation of all aspects of the anti-influenza immune responses will ultimately be necessary in the development of a successful broadly protective or universal influenza vaccine.

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Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

The FDA has approved Lutathera (lutetium Lu 177 dotatate) for the treatment adult patients with somatostatin receptor-positive GEP-NETs. Lutathera is a radioactive drug that works by binding to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells. This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs.

The approval of Lutathera was supported by two studies. The first was a randomized clinical trial in 229 patients with a certain type of advanced somatostatin receptor-positive GEP-NET. Patients in the trial either received Lutathera in combination with the drug octreotide or octreotide alone. The study measured the length of time the tumors did not grow after treatment (progression-free survival). Progression-free survival was longer for patients taking Lutathera with octreotide compared to patients who received octreotide alone. This means the risk of tumor growth or patient death was lower for patients who received Lutathera with octreotide compared to that of patients who received only octreotide.

The second study was based on data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who received Lutathera at a single site in the Netherlands. Complete or partial tumor shrinkage was reported in 16% of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA. Patients initially enrolled in the study received Lutathera as part of an expanded access program. Expanded access is a way for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives to gain access to investigational drugs for treatment use.

Common side effects of Lutathera include low levels of white blood cells (lymphopenia), high levels of enzymes in certain organs (increased GGT, AST and/or ALT), vomiting, nausea, high levels of blood sugar (hyperglycemia) and low levels of potassium in the blood (hypokalemia). Serious side effects of Lutathera include low levels of blood cells (myelosuppression), development of certain blood or bone marrow cancers (secondary myelodysplastic syndrome and leukemia), kidney damage (renal toxicity), liver damage (hepatotoxicity), abnormal levels of hormones in the body (neuroendocrine hormonal crises) and infertility. Lutathera can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lutathera are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.

Lutathera was granted Priority Review, under which the FDA’s goal is to take action on an application within six monthswhere the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lutathera also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lutathera to Advanced Accelerator Applications.

1. Put all of the above ingredients into the food processor and pulse until you have a very smooth creamy topping for the salad. If it’s too thick for your taste, just add a teaspoon at a time, of the freshly squeezed orange juice or coconut milk

2. Use this dressing/topping for the following fruit, when citrus is in season, which is right now.

3. Slice into circles and cut out the segments of all the different colors of citrus fruit that are now in season. Other fruit is added for flavor, health and color contrast

Blood oranges

Cara cara oranges

Pink grapefruit

Tangerines with interesting colors

A few blueberries

A few green seedless grapes

A few red seedless grapes

Chopped dates

1 heaping Tablespoon toasted then chopped walnuts

(Optional): Let all of the fruit soak in Grand Marnier for a few hours.

1 leaf of red lettuce on each salad plate or

1 leaf of red cabbage on each salad plate and/or

With a mandolin, run a section of red cabbage through once, and use the thin strands as a beautiful color contrast, healthy as well.

Arrange the leaf first, on individual salad plates, then place the fruit onto the leaf. Just before serving, add a big dollop of the dressing on the fruit. Garnish with a few toasted seeds and a fresh mint leaf.

Basically, I am supplying the recipe for dressing over citrus. Part of the fun of doing this easy, delicious salad,, is your creativity in arranging the fruit. I had fun with the citrus colors and the very thin streaks of red cabbage.